Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: Diminished compensatory mechanisms as a prelude to parkinsonism
Open accessAbstract
Aging is the most prominent risk factor for Parkinson's disease. Yet, consensus of how advancing age may predispose the dopamine (DA) system to parkinsonism is lacking. Three age ranges of female rhesus monkeys, 8-9, 15-17, and 21-31 years, received unilateral DA depletion with intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Morphological and biochemical analyses of DA-depleted and intact hemispheres revealed three primary findings: (1) The intact striatum exhibited age-related declines in dopamine (DA) and homovanillic acid (HVA) that were present by middle age; (2) In the MPTP-treated striatum, the compensatory increase in DA activity was absent in old monkeys; and (3) Age-associated morphological changes included declines in the density of tyrosine hydroxylase (TH) positive fibers in striatum, decreased nigral soma size, and optical density of TH, but no significant loss of neurons. These findings suggest that aging produces changes in the nigrostriatal DA system that approach the threshold for expression of parkinsonian features, and that progressive impairment of plasticity may be central to the role of aging in development of parkinsonism.
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α-Synuclein-induced abnormal upregulation of TH phosphorylation, combined with reduction of gene transcription by aging and aging-related disorders, accelerates pSer40-TH degradation to reduce total TH protein.
“The α-synuclein-induced abnormal upregulation of TH phosphorylation, combined with the reduction of gene transcription by aging and aging-related disorders [126,127,128,129], results in the acceleration of pSer40-TH degradation to reduce total TH protein (Figure 3).”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [126]
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- Authors
- Collier, T. J., Lipton, J., Daley, B. F., Palfi, S., Chu, Y., Sortwell, C., Bakay, R. A. E., Sladek, J. R., & Kordower, J. H.
- Affiliations
- University of Cincinnati (US)
- Rush University Medical Center (US)
- Corresponding author
- Collier, Timothy J.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2007-04
- Volume
- 26
- Issue
- 1
- Pages
- 56-65
- ISSN
- 0969-9961 (ISSN-L)
- PMC
- PMC1899875
- OpenAlex
- W2041046421
- Cited by
- 162
- References
- 35
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 14 · 2021: 4 · 2020: 12 · 2019: 1 · 2018: 12 · 2017: 7 · 2016: 7 · 2015: 4 · 2014: 12 · 2013: 7 · 2012: 10
- FWCI
- 10.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (AG17092)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- aging, Parkinson's disease, nigrostriatal dopamine system, MPTP, dopamine depletion, compensatory mechanisms, striatum, homovanillic acid, tyrosine hydroxylase, substantia nigra, rhesus monkeys, neuroplasticity, age-related decline
- MeSH terms
- Aging, Animals, Behavior, Animal, Brain, Chromatography, High Pressure Liquid, Dopamine, Female, Immunohistochemistry, Macaca mulatta, Motor Activity, Parkinson Disease, Secondary, Substantia Nigra, Tyrosine 3-Monooxygenase, Neostriatum, MPTP Poisoning
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